Tissue treatment

ABSTRACT

A method of treating tissue includes placing substantially spherical polymer particles in the tissue. The particles include an interior region having relatively large pores and a first region substantially surrounding the interior having fewer relatively large pores than the interior region.

CLAIM OF PRIORITY

[0001] This application is a continuation-in-part application of andclaims priority to U.S. patent application Ser. No. ______ [AttorneyDocket No. 01194-442001], entitled “Embolization” and filed on Aug. 9,2002, which is a continuation-in-part of U.S. Ser. No. 10/109,996, filedMar. 29, 2002. This application also claims priority to U.S. PatentApplication Serial No. 60/388,446, entitled “Bulking Agents” and filedon Jun. 12, 2002. The entire contents of both applications are herebyincorporated by reference.

TECHNICAL FIELD

[0002] This invention relates to the treatment of tissue, such as theintroduction of particles into body tissue for repair and/oraugmentation.

BACKGROUND

[0003] The body includes various passageways through which bodily matteror fluids, such as urine, can flow. The flow of material through thepassageways is in part affected by tissue surrounding the passageways.For example, the tissue can constrict and cause a passageway to narrowor to close, thereby restricting flow of material through thepassageway.

[0004] In some disorders, the tissue can no longer affect a passageway.For example, while urine normally flows down in one direction from thekidneys, through tubes called ureters, and to the bladder, invesicoureteral reflux (VUR), urine can flow abnormally from the bladderback into the ureters. In gastroesophageal reflux disease (GERD),sometimes called “reflux”, acid from the stomach can flow back into theswallowing tube, or esophagus. Other disorders include, for example,urinary incontinence, i.e., loss of urinary control, and fecalincontinence.

[0005] One method of treating such disorders includes placing, e.g.,injecting, a bulking material in the tissue adjacent to the passageway.The bulking material can narrow the passageway and, by providing bulk,allows the tissue to constrict the passageway more easily.

SUMMARY

[0006] This invention relates to the treatment of tissue.

[0007] In one aspect, the invention features a method of treating tissueincluding placing substantially spherical polymer particles in thetissue. The particles have an interior region having relatively largepores and a first region substantially surrounding the interior regionhaving fewer relatively large pores than the interior region.

[0008] Embodiments may include one or more of the following features.The particles are injected into the tissue. The particles are injectedpercutaneously. The particles are delivered through a catheter. Themethod includes forming a cavity in the tissue, and placing theparticles in the cavity. The tissue is adjacent to a body passageway.The passageway is defined by a ureter. The tissue is adjacent to a bodypassageway, and the particles are placed in an amount effective tonarrow the passageway.

[0009] The particles can be polyvinyl alcohol. The polyvinyl alcohol canbe 1,3 diol acetalized. The particles can include a polysaccharide. Thepolysaccharide can include alginate.

[0010] The particles can include a therapeutic agent.

[0011] In another aspect, the invention features a method of treating anindividual. The method includes placing a therapeutically effectiveamount of substantially spherical particles including polyvinyl alcoholin a tissue of the individual. The particles have an interior regionhaving relatively large pores and a first region substantiallysurrounding the interior region having fewer relatively large pores thanthe interior region.

[0012] Embodiments can include one or more of the following features.

[0013] The method further includes selecting the individual diagnosedwith gastroesophageal reflux disease. The tissue is adjacent to agastrointestinal tract. The method further includes selecting theindividual diagnosed with vesicoureteral reflux. The tissue is adjacentto a ureter.

[0014] The method can further include selecting an individual diagnosedwith urinary incontinence, fecal incontinence, intrinsic sphinctericdeficiency, and/or vocal cord paralysis. The method can further includeselecting an individual in need of a reconstructive or cosmeticprocedure.

[0015] The particles can be placed percutaneously and/or through acatheter.

[0016] In another aspect, the invention features a method of deliveringa therapeutically effective amount of substantially spherical polymerparticles. The particles include polyvinyl alcohol and include aninterior region having relatively large pores and a surface regionhaving fewer relatively large pores. The particles can have a diameterof about 1200 micron or less, a surface with a predominant pore size ofabout 2 micron or less and pores interior to surface of about 10 micronor more, and/or a surface region from about 0.8r to r, the predominantpore size in the surface region being smaller than the predominant poresize in a region C to 0.3r.

[0017] Embodiments may also include one or more of the following. Therelatively large pores are about 20 or 30 micron or more. The surfaceregion is about r to 0.8r. The surface region is about r to ⅔r. Theparticles include a body region from about ⅔r to r/3 includingintermediate size pores and the body region has more intermediate sizepores than the surface region. The center region is from about r/3 to C,the outer region including large size pores and the body region hasfewer large size pores than the center region. The intermediate sizepores are about 2 to 18 microns. The surface region is substantiallyfree of pores greater than about 5 micron.

[0018] Embodiments may also include one of the following. Thepredominant pore size progressively increases from surface to the centerof the particle. The predominant pore size on the particle surface isabout 1 micron or less. The particles have a surface region from about(2r)/3 to the surface wherein the predominant pore size is in the rangeof about 1 micron or less. The predominant pore size is about 0.1 micronor less. Interior of said surface region, the particles have apredominant pore size in the range of about 2 to 35 microns. Theparticles include a center region from about r to r/3 in which thepredominant pore size is about 20 to 35 micron. The particles have abody region from r/3 to (2r)/3 in which the predominant pore size isabout 2 to 18 micron. The particles have a surface region from about(2r)/3 to the periphery and the predominant pore size in the surfaceregion is about 10% or less than the predominant pore size in theinterior to the surface region. The particles include a surface regionfrom about 0.8r to r wherein the predominant pore size is about 1 micronor less. The particles include a region from about C to 0.8r includespores having a diameter of 10 microns or more. The region C to 0.8r hasa predominant pore size of about 3.5 to 2 micron. The particles have adensity of about 1.1 to about 1.4 g/cm3. The particles have a density ofabout 1.2 to 1.3 g/cm³. The particles have a sphericity of about 90% ormore. The particles have an initial sphericity of about 97% or more. Theparticles have a sphericity of about 0.90 after compression to about50%. The particles have a size uniformity of about ±15% or more.

[0019] Embodiments may also include one or more of the following. Theparticles include about 1% or less polysaccharide. The polysaccharide isalginate. The alginate has a guluronic acid content of about 60% orgreater. The particles are substantially insoluble in DMSO. Theparticles are substantially free of animal-derived compounds. Thepolyvinyl alcohol is composed of substantially unmodified polyvinylalcohol prepolymer. The polyvinyl alcohol is predominantly intrachain1,3-diols acetalized. The composition includes saline and/or contrastagent. The particles and/or composition are sterilized.

[0020] Embodiments may also include one or more of the following. Thegelling compound is a polysaccharide. The gelling compound is alginate.The alginate has a guluronic acid content of about 60% or more. Thedrops are contacted with a gelling agent. The gelling agent is adivalent cation. The cation is Ca+2. The base polymer is PVA. The PVA isreacted by acetalization. The PVA has a molecular weight of about 75,000g/mole or greater. The viscosity of the base polymer and gellingcompound is modified prior to forming said drops. The viscosity ismodified by heating. The drops are formed by vibratory nebulization.

[0021] Embodiments may also include one or more of the following.Administration is by percutaneous injection. Administration is by acatheter. The particles are introduced to the body through a lumen, andthe lumen has a smaller diameter than the particles.

[0022] The particles can be tailored to a particular application byvarying particle size, porosity gradient, compressibility, sphericityand density of the particles. The uniform size of the sphericalparticles can, for example, fit through the aperture of a needle or acatheter for administration by injection to a target site withoutpartially or completely plugging the lumen of the needle or thecatheter. Size uniformity of +15% of the spherical particles allows theparticles to stack evenly.

[0023] Embodiments may have one or more of the following advantages. Theparticles are relatively inert and biocompatible (e.g., they do nottrigger an allergic or cytotoxic response). The particles do notsubstantially migrate, which can cause adverse effects. The particlesare relatively non-bioresorbable. As a result, the particles retaintheir efficacy, and the need for repeated procedures is reduced, whichcan lower cost, trauma, and/or complications. The particles can be usedin a variety of applications.

[0024] Other aspects, features, and advantages of the invention will beapparent from the description of the preferred embodiments thereof andfrom the claims.

DESCRIPTION OF DRAWINGS

[0025]FIGS. 1A and 1B illustrate a method of treating tissue.

[0026]FIG. 2 illustrates a method of treating tissue.

[0027]FIG. 3A is a light micrograph of a collection of hydratedparticles; FIG. 3B is a scanning electron microscope (SEM) photograph ofthe particle surface; and FIGS. 3C-3E are cross-sections of theparticles.

[0028]FIG. 4A is a schematic of the manufacture of a composition; andFIG. 4B is an enlarged schematic of region A in FIG. 4A.

[0029]FIG. 5 is a photograph of gel-stabilized drops.

[0030]FIG. 6 is a graph of particle size uniformity.

[0031] FIGS. 7A-7F illustrate a method of treating tissue.

DETAILED DESCRIPTION

[0032] Referring to FIGS. 1A and 1B, a method of treating tissue 20,here, located adjacent to a passageway 22, is shown. Passageway 22 isdefined by a wall 24, e.g., of a urethra or a ureter. The methodgenerally includes placing a composition 27 including highly waterinsoluble, high molecular weight polymer particles 25 into tissue 20.Particles 25, e.g., acetalized polyvinyl alcohol, have a substantiallyuniform shape and a symmetric compressibility. Particles 25 can increasebulk and localize compression, thereby reducing the size of passageway22 and assisting tissue 20 in closing to reduce (e.g., minimize oreliminate) flow of matter, such as urine, through the passageway. Asdescribed below, composition 27 can include other materials, such as acarrier, a contrasting agent, and/or a therapeutic agent.

[0033] As shown, the method includes injecting composition 27 intotissue 20. Before composition 27 is injected, a cytoscope 26 isintroduced into passageway 22 by conventional cytoscopic techniques.Cytoscope 26 includes an elongated sheath 28 that defines a channel 30.In channel 30, cytoscope 26 includes a light emitting element 32 (suchas an optic fiber) and a viewing element 34. Cytoscope 26 is positionedat a location selected to view a target area 36 to be treated.

[0034] Subsequently, a needle 38 is inserted into tissue 20 to targetarea 36, but without penetrating wall 24. Composition 27 includingparticles 25 is then injected from a syringe (not shown) to area 36. Theprogress of the injection can be monitored, for example, by viewingchanges, e.g., narrowing, in passageway 22 through cytoscope 26 or byfluoroscopic or spectroscopic techniques, e.g., in embodiments in whichcomposition 27 includes a contrasting agent (described below). In otherembodiments, referring to FIG. 2, needle 38 is inserted through channel30 of cytoscope 26 to deliver composition 27.

[0035] The methods described above can be used for a variety of medicalapplications, such as for the treatment of intrinsic sphinctericdeficiency (ISD). For example, composition 27 can be used to treaturinary incontinence. Composition 27 can be injected into the tissue ofthe urinary tract, wherein the selected site can be, for example, themucosal tissue of the bladder neck, the urethra or urethral sphincter.The resulting bulking or augmentation of the urethral tissue can reduceor restrict the size of the urethra or urinary passage and thus assistin overcoming incontinence. Methods and techniques of placing bulkingmaterials for the treatment of urinary incontinence are described inNamiki, “Application of Teflon Paste for Urinary Incontinence—Report ofTwo Cases”, Urol. Int., Vol. 39, pp. 280-282 (1984); Politano et al.,“Periurethral Teflon Injection for Urinary Incontinence”, The Journal ofUrology, Vol. 111, pp. 180-183 (1974); Winters, et al., “PeriurethralInjection of Collagen in the Treatment of Intrinsic SphinctericDeficiency in the Female Patient”, Urologic Clinics of North America,22(3):473-478 (1995); U.S. Pat. Nos. 5,007,940; 5,158,573; 5,116,387;and references cited therein.

[0036] Composition 27 can be injected into the tissue of the anal canal,wherein the selected site can be, for example, the mucosal tissue of theanal canal, such as near the internal or external anal sphincter muscle.The resulting bulking or augmentation of the tissue can restrict thesize of the sphincter or anal passage and thus assist in reducing fecalor anal incontinence. Composition 27 can also be used to treat, e.g.,repair, structurally defective and/or inadequately functioning musclesof the anal sphincter. For example, a physician can perianally injectcomposition 27 into a deformity, e.g., a keyhole deformity resultingfrom trauma or surgery, using one or more injections, until thedeformity is repaired or the treated area is restored to its properform. Methods of placing biocompatible materials to treat the sphinctermuscles are described in Freed, U.S. Pat. No. 5,490,984.

[0037] Composition 27 can be used to treat vesicoureteral reflux. Forexample, composition 27 can be placed in the subureteral tissue tocompress the ureter, thereby reducing the reflux of urine into theureter. Methods for delivering a composition to treat vesicoureteralreflux are described in Capozza, et al., “Endoscopic Treatment ofVesico-Ureteric Reflux and Urinary Incontinence: Technical Problems inthe Pediatric Patient,” Br. J. Urol., 75: 538-542 (1995); and Smith etal., “Evaluation of Polydimethylsiloxane as an Alternative in theEndoscopic Treatment of Vesicoureteral Reflux”, J. Urol., 152:1221-1224, 1994.

[0038] Composition 27 can be applied to gastroesophageal reflux disease(GERD) applications. Composition 27 can be injected into the mucosaltissue of the upper gastrointestinal tract, wherein the selected sitemay be, for example, the mucosal tissue of the cardiac orifice of thestomach, which opens into the esophagus. The resulting bulking oraugmentation of the tissue can restrict the size of the passage and thusassist in reducing gastric fluids refluxing into the esophagus. Methodsand techniques are described, for example, in Shafik, “IntraesophagealPolytef Injection for the Treatment of Reflux Esophagitis”, Surg.Endoscopy, 10:329-331 (1996), and references cited therein.

[0039] Composition 27 can also be used to treat other conditions, suchas vocal cord paralysis, e.g., to restore glottic competence in cases ofparalytic dysphonia. Such general treatment methods are described inHirano et al., “Transcutaneous Intrafold Injection for Unilateral VocalCord Paralysis: Functional Results”, Ann. Otol. Rhinol. Laryngol., Vol.99, pp. 598-604 (1990); Strasnick et al., “Transcutaneous Teflon®Injection for Unilateral Vocal Cord Paralysis: An Update”, Laryngoscope,Vol. 101, pp. 785-787 (July 1991); and references cited therein.

[0040] In other embodiments, composition 27 is used to treat softtissue. For example, composition 27 can be used for reconstructive orcosmetic applications, e.g., surgery. Examples of applications includereconstruction of cleft lips; scars, e.g., depressed scars from chickenpox or acne scars; indentations resulting from liposuction; wrinkles,e.g., glabella frown wrinkles; and soft tissue augmentation of thinlips. Composition 27 can be used as a graft material or a filler to filland/or to smooth out soft tissue defects. For example, composition 27can be injected percutaneously under a defect until the appearance ofthe defect, e.g., a wrinkle, is reduced. Procedures and techniques aredescribe, for example, in Ersek et al., “Bioplastique: A New TexturedCopolymer Microparticles Promises Permanence in Soft-TissueAugmentation”, Plastic and Reconstructive Surgery, Vol. 87, No. 4, pp693-702 (April 1991); Lemperle et al., “PMMA Microspheres forIntradermal Implantation: Part I. Animal Research”, Annals of PlasticSurgery, Vol. 26, No. 1, pp. 57-63 (1991); and references cited therein.

[0041] For the applications described above, the amount of composition27 delivered can vary based on the nature, location and severity of thecondition to be treated and the route of administration, the size ofparticles 25, and factors relating to the patient. A physician treatingthe condition, disease or disorder can determine an effective amount ofcomposition 27. An effective amount of composition 27 refers to theamount sufficient to result in amelioration of symptoms or aprolongation of survival of the patient.

[0042] In other embodiments, particles 25 can also be used forimplantable prostheses, such as mammary or breast implants, penileimplants, or testicular prostheses. For example, particles 25 can beencased in a shell made of compliant material, such as siliconeelastomers, polyolefins, polyurethanes, ethylene-propylene dienemonomers, or ethylene-propylene rubbers. In embodiments, particles 25can be used without a shell because they can remain at the delivery siteand do not migrate. Prostheses are described, for example, in U.S. Pat.Nos. 5,941,909; 6,060,639; 5,063,914; and references cited therein.

The Composition

[0043] As described above, composition 27 includes polymer particles 25.In embodiments, composition 27 also includes a carrier, a contrastingagent, and/or a therapeutic agent.

[0044] The particles: Particles 25 are substantially formed of polymersuch as a highly water insoluble, high molecular weight polymer. As willbe discussed below, a preferred polymer is high molecular weightpolyvinyl alcohol (PVA) that has been acetalized. Preferably, theparticles are substantially pure intrachain 1,3 acetalized PVA andsubstantially free of animal derived residue such as collagen. Inembodiments, the particles include a minor amount, e.g. less than about0.2 weight %, of alginate or another polysaccharide or gelling material.

[0045] Referring to FIG. 3A, particles 111 have a substantially uniformspherical shape and size. Referring to FIG. 3B, each particle has awell-defined outer spherical surface including relatively small,randomly located pores. The surface appears substantially smooth, withsome larger surface morphology such as crevice-like features. Referringto FIGS. 3C-3E, SEM images of cross-sections through particles, the bodyof the particle defines pores which provide compressibility and otherproperties. Pores near the center of the particle are relatively largeand pores near the surface of the particle are relatively small.

[0046] The region of small pores near the periphery of the particle isrelatively stiff and incompressible, which enhances resistance to shearforces and abrasion. In addition, the variable pore size profileproduces a symmetric compressibility and, it is believed, acompressibility profile such that the particles are relatively easilycompressed from a maximum, at rest diameter to a smaller, compressedfirst diameter but compression to even smaller diameter requiressubstantially greater force. A variable compressibility profile isbelieved to be due to the presence of a relative weak, collapsibleinter-pore wall structure in the center region where the pores arelarge, and a stiffer inter-pore wall structure near the surface of theparticle, where the pores are more numerous and relatively small. Thevariable pore size profile also is believed to enhance elastic recoveryafter compression. The pore structure also influences the density of theparticles and the rate of carrier fluid or body fluid uptake.

[0047] The particles can be delivered through a needle having a lumenarea that is smaller, e.g. 50% smaller or less, than the uncompressedcross-sectional area of the particles. As a result, the particles arecompressed to pass through the needle for delivery into the body. Thecompression force is provided indirectly by increasing the pressureapplied to the carrier fluid by depressing the syringe plunger. Theparticles are relatively easily compressed to diameters sufficient fordelivery through the needle into the body. The robust, rigid surfaceregion resists abrasion when the particles contact hard surfaces such assyringe surfaces, and the needle lumen wall (e.g. stainless steel)during delivery. Once in the body, the particles substantially recoverto original diameter and shape, and form a dense mass. The compressioncan be limited by the compression profile of the particles, and thenumber of particles needed at a particular target area can be reduced.

[0048] In embodiments, the particles have a diameter of about 1500 or1200 microns or less, and about 10 microns or more, e.g. about 400microns or more and the pores are about 50 or 35 to 0.01 micron. Theparticles can be classified in size ranges of about 500-700 microns,about 700-900 microns, or about 900-1200 microns. The particlestypically have a mean diameter in approximately the middle of the rangeand variance of about 20% or less, e.g. 15% or 10% or less.

[0049] The particular size of the particles used can also be a functionof their application. For example, for cosmetic applications, relativelysmall particles can be used to provide a more natural feel and to reducea granular texture. Small particles can also be delivered through smallneedles, which can reduce psychological trauma and discomfort to thepatient.

[0050] Referring particularly to FIG. 3C, the particles can beconsidered to include a center region, C, from the center of theparticle to a radius of about r/3, a body region, B, from about r/3 toabout 2 r/3 and a surface region, S, from 2r/3 to r. The regions can becharacterized by the relative size of the pores and the number of poresof given sizes. In embodiments, the center region has a greater numberof relatively large pores than the body region and the surface region.The large pores are in the range of about 20 micron or more, e.g. 30micron or more, or in the range of about 20 to 35 micron. The bodyregion has a greater number of intermediate size pores than the surfaceregion. The intermediate size pores are in the range of about 5 to 18micron. In embodiments, the regions may also have different densities,with the density of the surface region being greater than the density ofthe body region, and the density of the body region being greater thanthe density of the center region.

[0051] The size of the pores in each of the regions can also becharacterized by a distribution. In embodiments, the predominant poresize(s) in the center region being greater than the predominant poresize(s) in the body region and the predominant pore size(s) in the bodyregion is greater than the predominant pore size(s) in the surfaceregion. In embodiments, in the predominant pore size in the centerregion is 20 micron or more, e.g. 30 microns or more, or in the range ofabout 20 to 35 microns. The predominant pore size in the body region isabout 18 micron or less, e.g. about 15 micron or less, or in the rangeof about 18 to 2 micron. The pores in the surface region are preferablypredominantly less than about 1 micron, e.g. about 0.1 to 0.01 micron.

[0052] In embodiments, the predominant pore size in the body region isabout 50 to 70% of the pore size in the center region and the pore sizein the surface region is about 10% or less, e.g. about 2% of the poresize in the body region. The size of the pores on the outer surface ofthe particle is predominantly in the range of about 1 micron or less,e.g. about 0.1 or 0.01 micron. In embodiments, the surface and/orsurface region is substantially free of pores having a diameter largerthan about 10 micron or larger than about 1 micron. In embodiments, thepredominant pore size is in the region 0.8 or 0.9r to r is about 1micron or less, e.g. 0.5 to 0.1 micron or less. The region from thecenter of the particle to 0.8 or 0.9r has pores of about 10 micron orgreater and/or has a predominant pore size of about 2 to 35 micron. Inembodiments, the predominant pore size in the region 0.8 or 0.9r to r isabout 5% or less, e.g. 1% or 0.3% or less than the predominant pore sizein the region from the center to 0.9r. the largest pores in theparticles can have a size in the range of 1% or 5% or 10% or more of theparticle diameter.

[0053] The size of the pores can be measured by viewing a cross-sectionas in FIG. 3C. For irregularly shaped pores, the maximum visiblecross-section is used. The predominant pore size(s) can be found bymeasuring the size of the visible pores and plotting the number of poresas a function of size. The predominant pore size(s) are the sizes thatare about the maximum in the distribution. In FIG. 3C, the SEM was takenon wet particles including absorbed saline, which were frozen in liquidnitrogen and sectioned. (FIG. 3B was taken prior to sectioning.) InFIGS. 3D and 3E, the particle was freeze-dried prior to sectioning andSEM analysis.

[0054] Referring to FIG. 4A, a system for manufacturing particlesincludes a flow controller 300, a drop generator 310, a gelling vessel320, a reactor vessel 330, a gel dissolution chamber 340 and a filter350. The flow controller 300 delivers polymer solutions to a viscositycontroller 305, which heats the solution to reduce viscosity prior todelivery to the drop generator 310. The drop generator 310 forms anddirects drops into a gelling vessel 320, where drops are stabilized bygel formation. The gel-stabilized drops are transferred from the gellingvessel 320 to reactor vessel 330 where the polymer in the gel-stabilizeddrops is reacted forming precursor particles. The precursor particlesare transferred to a gel dissolution chamber 340, where the gel isdissolved. The particles are then filtered in a filter 350 to removedebris, sterilized, and packaged.

[0055] A base polymer and a gelling precursor are dissolved in water andmixed. The mixture is introduced to a high pressure pumping apparatus,such as a syringe pump (e.g., model PHD4400, Harvard Apparatus,Holliston, Mass.). Examples of base polymers include polyvinyl alcohol,polyacrylic acid, polymethacrylic acid, poly vinyl sulfonate,carboxymethyl cellulose, hydroxyethyl cellulose, substituted cellulose,polyacrylamide, polyethylene glycol, polyamides, polyureas,polyurethanes, polyester, polyethers, polystyrene, polysaccharide,polylactic acid, polyethylene, polymethylmethacrylate and copolymers ormixtures thereof. A preferred polymer is polyvinyl alcohol. Thepolyvinyl alcohol, in particular, is hydrolyzed in the range of 80 to99%. The weight average molecular weight of the base polymer can be inthe range of 9000 to 186,000, 85,000 to 146,000 or 89,000 to 98,000.Gelling precursors include, for example, alginates, alginate salts,xanthan gums, natural gum, agar, agarose, chitosan, carrageenan,fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gumghatti, gum karaya, gum tragacanth, hyaluronic acid, locust beam gum,arabinogalactan, pectin, amylopectin, other water solublepolysaccharides and other ionically crosslinkable polymers. A particulargelling precursor is sodium alginate. A preferred sodium alginate ishigh guluronic acid, stem-derived alginate (e.g. about 50 or 60% or moreguluronic acid with a low viscosity e.g. about 20 to 80 cps at 20° C.)which produces a high tensile, robust gel. High molecular weight PVA isdissolved in water by heating, typically above about 70° C., whilealginates can be dissolved at room temperature. The PVA can be dissolvedby mixing PVA and alginate together in a vessel which is heated toautoclave temperature (about 121° C.). Alternatively, the PVA can bedisposed in water and heated and the alginate subsequently added at roomtemperature to avoid exposing the alginate to high temperature. Heat canalso be applied by microwave application. In embodiments, forPVA/alginate, the mixture is typically about 7.5 to 8.5%, e.g. about 8%by weight PVA and about 1.5 to 2.5%, e.g. about 2%, by weight alginate.

[0056] Referring to FIG. 4B, the viscosity controller 305 is a heatexchanger circulating water at a predetermined temperature about theflow tubing between the pump and drop generator. The mixture of basepolymer and gelling precursor flows into the viscosity controller 305,where the mixture is heated so that its viscosity is lowered to a levelfor efficient formation of very small drops. For a high molecular weightPVA/alginate solution, the temperature of the circulating water is lessthan about 75° C. and more than about 60° C., for example, 65° C. whichmaintains the mixture at a viscosity of 90-200 centipoise. For sphericalparticles, the viscosity of the drops is maintained so they are capturedin the gelling vessel without splintering or cojoining which can createirregular, fiberous particles. In other embodiments, the flow controllerand/or the drop generator can be placed in a temperature-controlledchamber, e.g. an oven, or a heat tape wrap, to maintain a desiredviscosity.

[0057] The drop generator 310 generates substantially spherical drops ofpredetermined diameter by forcing a stream of the mixture of basepolymer and gelling precursor through a nozzle which is subject to aperiodic disturbance to break up the jet stream into drops. The jetstream can be broken into drops by vibratory action generated forexample, by an electrostatic or piezoelectric element. The drop size iscontrolled by controlling the flow rate, viscosity, amplitude, andfrequency at which the element is driven. Lower flow rates and higherfrequencies produce smaller drops. A suitable electrostatic dropgenerator is available from NISCO Engineering, model NISCO Encapsulationunit VAR D, Zurich, Switzerland. In embodiments, the frequency is in therange of about 0.1 to 0.8 kHz. The flow rate through the dropletgenerator is in the range of about 1 to 12 mL per minute. The dropgenerator can include charging the drops after formation such thatmutual repulsion between drops prevents drop aggregation as drops travelfrom the generator to the gelling vessels. Charging may be achieved by,e.g. an electrostatic charging device such as a charged ring positioneddownstream of the nozzle.

[0058] Drops of the base polymer and gelling precursor mixture arecaptured in the gelling vessel 320. The gelling vessel 320 contains agelling agent which interacts with the gelling precursor to stabilizedrops by forming a stable gel. Suitable gelling agents include, forexample, a divalent cation such as alkali metal salt, alkaline earthmetal salt or a transition metal salt that can ionically crosslink withthe gelling agent. An inorganic salt, for example, a calcium, barium,zinc or magnesium salt can be used as a gelling agent. In embodiments,particularly those using an alginate gelling precursor, a suitablegelling agent is calcium chloride. The calcium cations have an affinityfor carboxylic groups in the gelling precursor. The cations complex withcarboxylic groups in the gelling precursor resulting in encapsulation ofthe base polymer in a matrix of gelling precursor.

[0059] Referring to FIG. 5, a photo-image of the gelled particles, thegelling agent is in an amount selected in accordance with the desiredproperties of the particles. As evident, a pore structure in theparticle forms in the gelling stage. The concentration of the gellingagent can control pore formation in the particle, thereby controllingthe porosity gradient in the particle. Adding non-gelling ions, forexample, sodium ions, to the gelling solution can reduce the porositygradient, resulting in a more uniform intermediate porosity throughoutthe particle. In embodiments, the gelling agent is, for example, 0.01-10weight percent, 1-5 weight percent or 2 weight percent in deionizedwater. In embodiments, particles, including gelling agent and a porestructure can be used in composition 27.

[0060] Following drop stabilization, the gelling solution is decantedfrom the solid drops and the stabilized drops are transferred to thereactor vessel 330. In the reactor vessel 330, the stabilized drops arereacted to produce precursor particles. The reactor vessel includes anagent that chemically reacts with the base polymer, e.g. to causecrosslinking between polymer chains and/or within a polymer chain. Theagent diffuses into the stabilized drops from the surface of theparticle in a gradient which, it is believed, provides more crosslinkingnear the surface of the stabilized drop compared to the body and centerof the drop. Reaction is greatest at the surface of the drop, providinga stiff, abrasion resistant exterior. For polyvinyl alcohol, forexample, the vessel 330 includes aldehydes, such as formaldehyde,glyoxal, benzaldehyde, aterephthalaldehyde, succinaldehyde andglutaraldehyde for the acetalization of polyvinyl alcohol. The vessel330 also includes an acid, for example, strong acids such as sulfuricacid, hydrochloric acid, nitric acid and weak acids such as acetic acid,formic acid and phosphoric acid. In embodiments, the reaction isprimarily a 1,3 acetalization:

[0061] This intra-chain acetalization reaction can be carried out withrelatively low probability of inter-chain crosslinking as described inJohn G. Pritchard “Poly(Vinyl Alcohol) Basic Properties And Uses(Polymer Monograph, vol. 4) (see p. 93-97), Gordon and Breach, SciencePublishers LTD., London, 1970, the entire contents of which is herebyincorporated by reference. Some OH groups along a polymer chain canremain unconverted since the reaction proceeds in a random fashion andthere can be left over OH groups that do not react with adjacent groups.

[0062] Adjusting the amount of aldehyde and acid used, reaction time andreaction temperature can control the degree of acetalization. Inembodiments, the reaction time is e.g., 5 minutes to 1 hour, 10 to 40minutes or 20 minutes. The reaction temperature can be 25° C. to 150° C.or 75° C. to 130° C. or 65° C. The reactor vessel is placed in a waterbath fitted with an orbital motion mixer. The crosslinked precursorparticles are washed several times with deionized water to neutralizethe particles and remove any residual acidic solution.

[0063] The precursor particles are transferred to the dissolutionchamber 340 to remove the gelling precursor, e.g. by an ion exchangereaction. In embodiments, sodium alginate is removed by ion exchangewith a solution of sodium hexa-metaphosphate (EM Science). The solutioncan include, for example, ethylenediaminetetraacetic acid (EDTA), citricacid, other acids and phosphates. The concentration of the sodiumhexa-metaphosphate can be, for example, 1-20 weight %, 1-10 weight % or5 weight % in deionized water. Residual gelling precursor, for example,sodium alginate, can be determined by assay for detection of uronicacids in, for example, alginates containing mannuronic and guluronicacid residues. Suitable assays include rinsing the particles with sodiumtetraborate in sulfuric acid solution to extract alginate and combiningthe extract with metahydroxydiphenyl colormetric reagent and determiningconcentration by UV/VIS spectroscopy. Testing can be carried out byalginate suppliers such as FMC Biopolymer, Oslo, Norway. Residualalginate can be present in the range of about 20-35% by weight prior torinsing and in the range of about 0.01-0.5% or 0.1-0.3% or 0.18% in theparticles after rinsing for 30 minutes in water at about 23° C.

[0064] The particles are filtered through filter 350 to remove residualdebris. Particles of 500 to 700 microns are filtered through a sieve of710 microns and then a sieve of 300 microns. Particles of 700 to 900microns are filtered through a sieve of 1000 microns and then a sieve of500 microns. Particles of 900 to 1200 microns are filtered through asieve of 1180 microns and then a sieve of 710 microns.

[0065] The filtered particles are sterilized by a low temperaturetechnique such as e-beam irradiation, and packaged. In embodiments,electron beam irradiation can be used to pharmaceutically sterilize theparticles to reduce bioburden. In e-beam sterilization, an electron beamis accelerated using magnetic and electric fields, and focused into abeam of energy. This resultant beam can be scanned by means of anelectromagnet to produce a “curtain” of accelerated electrons. Theaccelerated electron beam penetrates the collection of particles toconfer upon them electrons which destroy bacteria and mold to sterilizeand reduce the bioburden in the particles. Electron beam sterilizationcan be performed by sterilization vendors, such as Titan Scan, Lima,Ohio.

[0066] Additional information about the particles is described incommonly assigned U.S. Ser. No. ______ [Attorney Docket No.01194-442001], filed Aug. 9, 2002, and entitled “Embolization”, herebyincorporated by reference in its entirety.

[0067] The following example is illustrative and not intended to belimiting.

EXAMPLE

[0068] Particles are manufactured from an aqueous solution containing 8weight % of polyvinyl alcohol, 99+% hydrolyzed, average M_(w)89,000-120,000 (ALDRICH) and 2 weight % of gelling precursor, sodiumalginate, PRONOVA UPLVG, (FMC BioPolymer, Princeton, N.J.) in deionizedwater and the mixture is heated to about 121° C. The solution has aviscosity of about 310 centipoise at room temperature and a viscosity ofabout 160 cps at 65° C. Using a syringe pump (Harvard Apparatus), themixture is fed to drop generator (Nisco Engineering). Drops are directedinto a gelling vessel containing 2 weight % of calcium chloride indeionized water and stirred with a stirring bar. The calcium chloridesolution is decanted within about three minutes to avoid substantialleaching of the polyvinyl alcohol from the drops into the solution. Thedrops are added to the reaction vessel containing a solution of 4% byweight of formaldehyde (37 wt % in methanol) and 20% by weight sulfuricacid (95-98% concentrated). The reaction solution is stirred at 65° C.for 20 minutes. Precursor particles are rinsed with deionized water(3×300 mL) to remove residual acidic solution. The sodium alginate issubstantially removed by soaking the precursor particles in a solutionof 5 weight % of sodium hexa-methaphosphate in deionized water for 0.5hour. The solution is rinsed in deionized water to remove residualphosphate and alginate. The particles are filtered by sieving, asdiscussed above, placed in saline (USP 0.9% NaCl) and followed byirradiation sterilization.

[0069] Particles were produced at the nozzle diameters, nozzlefrequencies and flow rates (amplitude about 80% of maximum) described inTable 1. TABLE 1 Nozzle Suspend- Bead Size Diameter Frequency Flow RateDensity ability (microns) (microns) (kHz) (mL/min) (g/mL) Sphericity(minutes) 500-700  150 0.45 4 — 0.92 3 700-900  200 0.21 5 1.265 0.94 5900-1200 300 0.22 10 — 0.95 6

[0070] Suspendability is measured at room temperature by mixing asolution of 2 ml of particles in 5 ml saline with contrast solution(Omnipaque 300, Nycomed, Buckinghamshire, UK) and observing the time forabout 50% of the particles to enter suspension, i.e. have not sunk tothe bottom or floated to the top of a container (about 10 ml, 25 mmdiameter vial). Suspendability provides a practical measure of how longthe particles will remain suspended. (Omnipaque is an aqueous solutionof Iohexol, N.N.-Bis(2,3-dihydroxypropyl)-T-[N-(2,3-dihydroxypropyl)-acetamide]-2,4,6-trilodo-isophthalamide;Omnipaque 300 contains 647 mg of iohexol equivalent to 300 mg of organiciodine per ml. The specific gravity of 1.349 of 37° C. and an absoluteviscosity 11.8 cp at 20° C.) The particles remain in suspension forabout 2 to 3 minutes.

[0071] Particle size uniformity and sphericity is measured using aBeckman Coulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter,Miami, Fla.). Briefly, the RapidVUE takes an image of continuous-tone(gray-scale) form and converts it to a digital form through the processof sampling and quantization. The system software identifies andmeasures particles in an image in the form of a fiber, rod or sphere.Sphericity computation and other statistical definitions are in AppendixA, attached, which is a page from the RapidVUE operating manual.

[0072] Referring to FIG. 6, particle size uniformity is illustrated forparticles 700-900 micron. The x-axis is the particle diameter. They-axis is the volume normalized percentage of particles at each particlesize. The total volume of particles detected is computed and the volumeof the particles at each diameter is divided by the total volume. Theparticles have distribution of particle sizes with variance of less thanabout ±15%.

[0073] While substantially spherical particles are preferred,non-spherical particles can be manufactured and formed by controlling,e.g., drop formation conditions or by post-processing the particles,e.g. by cutting or dicing into other shapes. Particles can also beshaped by physical deformation followed by crosslinking. Particleshaping is described in U.S. Ser. No. 10/116,330, filed Apr. 4, 2002.

[0074] Carrier: Composition 27 can include one or more carrier materialsthat allow the composition to be delivered in a first state, e.g., arelatively fluid or low viscosity state, and change, e.g., by phasetransition, to a second state, e.g., a relatively high viscosity orrigid state. In embodiments, particles 25 can be suspended in abiocompatible, resorbable lubricant, such as a cellulose polysaccharidegel having water, glycerin and sodium carboxymethylcellulose. The gelenables particles 25 to remain in suspension without settling. Otherpolysaccharides can also be included such as cellulose, agarmethylcellulose, hydroxypropyl methylcellulose, ethylcellulose,microcrystalline cellulose, oxidized cellulose, and other equivalentmaterials.

[0075] The polysaccharide gel is biocompatible, and the lubriciousnature of the polysaccharide gel can reduce the frictional forcesgenerated during the transferring of the particles from a syringe byinjection into the tissue site. In addition, polysaccharides do notgenerate an antigenic response, and the polysaccharide gel is readilysterilizable and stable at ambient conditions and does not needrefrigeration for storage and shipment.

[0076] After injection of composition 27 into the tissue, thepolysaccharide gel can be resorbed by the tissue, leaving thenon-resorbable matrix of particles 25 in place in the particular area orbolus, where it can remain without migrating to other areas of the body.

[0077] Other examples of carriers include undiluted agarose, methylcellulose or other linear unbranched polysaccharide, dextran sulfate,succinylated non-crosslinked collagen, methylated non-crosslinkedcollagen, glycogen, dextrose, maltose, triglycerides of fatty acids, eggyolk phospholipids, heparin, DMSO, phosphate buffered saline, and thelike. Examples of collagen are described in U.S. Pat. No. 5,490,984.More examples of appropriate carriers include hyaluronic acid, polyvinylpyrrolidone or a hydrogel derived thereof, dextran or a hydrogelderivative thereof, glycerol, polyethylene glycol, succinylatedcollagen, liquid collagen, oil based emulsions such as corn oil orsafflower, B-D glucose (or B-glucan, as described in U.S. Pat. No.6,277,392) or other polysachaarides or biocompatible organic polymerseither singly or in combination with one or more of the above materials.

[0078] Hydrogel compositions, such as those that swell upon injectioninto tissue due to hydration by physicologic fluid, are described, forexample, in U.S. Pat. Nos. 6,423,332; 6,306,418; and 5,902,832. Inembodiments, the composition can swell from an initial dehydrated volumeto a final hydrated volume that is substantially the same as the initialtotal volume of composition injected into the tissue to be treated.Examples include poly(ethylene oxide), polyvinyl pyrrolidone, polyvinylalcohol, poly(propylene oxide), poly(ethylene, glycol), poly(propyleneglycol), polytetramethylene oxide, polyacrylamide, poly(hydroxy ethylacrylate), poly(hydroxy ethyl methacrylate), hydroxy ethyl cellulose,hydroxy propyl cellulose, methoxylated pectin gels, agar, a starch suchas cornstarch, a modified starch, an alginate, a hydroxy ethylcarbohydrate, or the like and should preferably be adjusted so as toallow swelling to a selected percent after hydration. The carrier candisperse over time.

[0079] In some embodiments, composition 27 includes between about 0.5 toabout 50 weight percent of the carrier. For example, composition 27 caninclude greater than or equal to about 0.5, 5, 10, 15, 20, 25, 30, 35,40, or 45 weight percent of the carrier; and/or less than or equal toabout 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 weight percent of thecarrier.

[0080] Contrasting agent: In embodiments, composition 27 includes acontrasting agent. The contrast agent can be a biocompatible materialcapable of being monitored during injection by, for example,radiography, fluoroscopy, ultrasound, or visually. The contrast agentcan be water soluble or water insoluble. Examples of water solublecontrast agents include metrizamide, iopamidol, iothalamate sodium,iodomide sodium, and meglumine. Examples of water insoluble contrastagents include tantalum, tantalum oxide, and barium sulfate, each ofwhich is available in a form for in vivo use including a particle sizeof about 10 microns or less. Other water insoluble contrast agentsinclude gold, tungsten, and platinum powders.

[0081] Some examples of radiopaque materials include paramagneticmaterials (e.g. persistent free radicals) and compounds, salts, andcomplexes of paramagnetic metal species (e.g., transition metal orlanthanide ions); heavy atom (e.g., atomic number of 37 or more)compounds, salts, or complexes (e.g., heavy metal compounds, iodinatedcompounds, etc.); radionuclide-containing compounds, salts, or complexes(e.g. salts, compounds or complexes of radioactive metal isotopes orradiodinated organic compounds); and superparamagentic materials (e.g.,metal oxide or mixed oxide particles, particularly iron oxides).Paramagnetic metals include Gd (III), Dy (III), Fe (III), Fe (III), Mn(III) and Ho (III), and paramagnetic Ni, Co and Eu species. Heavy metalsinclude Pb, Ba, Ag, Au, W, Cu, Bi and lanthanides such as Gd. Metals,metal oxides, and alloys, including but not limited to medical gradestainless steel, silver, gold, titanium and titanium alloys, oxidederivatives of stainless steel or titanium or titanium alloys, aluminumoxide, and zirconium oxide can also be used. The amount of contrastingagent used can be any amount sufficient to be detected.

[0082] Therapeutic agent: In embodiments, particles 25 include one ormore therapeutic agents. For example, an effective amount of woundhealing agents can be added to composition 27. These agents includeprotein growth factors such as fibroblast growth factors (FGFs),platelet derived growth factors (PDGFs), epidermal growth factors(EGFs), connective tissue activated peptides (CTAPs), transforminggrowth factors (TGFs), and the like. The amount of wound healingagent(s) to be included with composition 27 can vary, depending, forexample, on the patient (age, sex, medical history) and the site beingtreated. In embodiments, composition 27 includes antimicrobial additivesand/or antibodies to reduce the potential for infection at the treatmentsite. Other agents are described in commonly assigned U.S. Ser. No.______ [Attorney Docket No. 01194-438001], filed on Aug. 30, 2002, andentitled “Drug Delivery Particles”. The therapeutic agent can be addedto composition 27 and/or be placed on particles 25.

[0083] Other additives: Composition 27 can include one or more materialsthat enhance the mechanical and/or physical properties of thecomposition. In some embodiments, particles 25 can be combined with oneor more relatively hard materials. The relatively hard material can be,for example, biocompatible ceramics, biocompatible metals (e.g.,stainless steel), glass, or other biocompatible materials such ascalcium salts, e.g., hydroxyapatite. The combination of particles 25 andhard material(s) can be used, for example, to fill depressed scars,unsymmetrical orbital floors, or bone defects in reconstructive surgicalprocedures.

[0084] Other methods can be used to placed particles 25 and/orcomposition 27 into tissue. For example, particles 25 and/or composition27 can be placed laproscopically. Particles 25 and/or composition 27 canalso be placed in a cavity or void created in tissue.

[0085] Referring to FIGS. 7A-7F, a method of placing particles 25 and/orcomposition 27 is shown. The method includes using a catheter or asheath 402, e.g., a blunt-ended hypotube, configured to proximallyreceive a penetration device 404, e.g., one having a trocar at itsdistal end. Penetration device 404 is inserted into sheath 402 to allowthe sheath to penetrate into tissue 403 (FIG. 7A). In embodiments, thepenetration depth can be determined by striping 406 formed on sheath402. For example, the tip of penetration device 404 can penetrate about2-2.5 cm into tissue 403, while the tip of sheath 402 can penetrateabout 0.5-1 cm into the tissue. After penetration of tissue 403,penetration device 404 is withdrawn from sheath 402, which is retainedpenetrated in the tissue (FIG. 7B).

[0086] A catheter 406 carrying an uninflated balloon 408 at the distalend is then inserted into sheath 402 (FIG. 7C) such that the balloonextends into tissue 403. Balloon 408 is then inflated using an inflationdevice, such as a syringe 410 containing saline (FIG. 7D). As balloon408 inflates, it creates a cavity or a void 412 in tissue 403. Inembodiments, balloon 408 is shaped to provide a cavity with apredetermined shape. Balloon 408 is then deflated, and catheter 406 iswithdrawn from sheath 402 (FIG. 7E). An injection device 414, such as asyringe 416 containing particles 25 and/or composition 27, is theninserted into sheath 402, and the particles and/or composition can bedelivered to cavity 412 (FIG. 7F).

[0087] In other embodiments, particles 25 and/or composition 27 can beused with a device, such as an indwelling sling, used to treat urinaryincontinence. An example of a device is described in WO 00/74633.Particles 25 and/or composition 27 can be placed, e.g., injected, intothe device as a bulking agent to provide lift, thereby providing anothermethod of adjusting the degree of support provided by the device.

[0088] All publications, references, applications, and patents referredto herein are incorporated by reference in their entirety.

[0089] Other embodiments are within the claims.

What is claimed is:
 1. A method of treating tissue, the methodcomprising: placing substantially spherical polymer particles in thetissue, the particles having an interior region comprising relativelylarge pores and a first region substantially surrounding the interiorregion comprising fewer relatively large pores than the interior region.2. The method of claim 1, wherein the particles are injected into thetissue.
 3. The method of claim 2, wherein the particles are injectedpercutaneously.
 4. The method of claim 1, wherein the particles aredelivered through a catheter.
 5. The method of claim 1, comprisingforming a cavity in the tissue, and placing the particles in the cavity.6. The method of claim 1, wherein the tissue is adjacent to a bodypassageway.
 7. The method of claim 6, wherein the passageway is definedby a ureter.
 8. The method of claim 1, wherein the tissue is adjacent toa body passageway, the particles being placed in an amount effective tonarrow the passageway.
 9. The method of claim 1, wherein the particlescomprise polyvinyl alcohol.
 10. The method of claim 9, wherein thepolyvinyl alcohol is 1,3 diol acetalized.
 11. The method of claim 9,wherein the particles comprise a polysaccharide.
 12. The method of claim9, wherein the polysaccharide comprises alginate.
 13. The method ofclaim 1, wherein the particles comprise a therapeutic agent.
 14. Amethod of treating an individual, the method comprising: placing atherapeutically effective amount of substantially spherical particlescomprising polyvinyl alcohol in a tissue of the individual, theparticles having an interior region comprising relatively large poresand a first region substantially surrounding the interior regioncomprising fewer relatively large pores than the interior region. 15.The method of claim 14, further comprising selecting the individualdiagnosed with gastroesophageal reflux disease.
 16. The method of claim15, wherein the tissue is adjacent to a gastrointestinal tract.
 17. Themethod of claim 14, further comprising selecting the individualdiagnosed with vesicoureteral reflux.
 18. The method of claim 17,wherein the tissue is adjacent to a ureter.
 19. The method of claim 14,further comprising selecting the individual diagnosed with urinaryincontinence.
 20. The method of claim 14, further comprising selectingthe individual diagnosed with fecal incontinence.
 21. The method ofclaim 14, wherein the particles are placed percutaneously.
 22. Themethod of claim 14, wherein the particles are placed through a catheter.23. The method of claim 14, further comprising selecting the individualdiagnosed with instrinsic sphincteric deficiency.
 24. The method ofclaim 14, further comprising selecting the individual diagnosed withvocal cord paralysis.
 25. The method of claim 14, further comprisingselecting the individual in need of a reconstructive or cosmeticprocedure.